Genentech / Roche put out a press release this morning about the German CLL11 study that we have talked about several times previously. American Society of Hematology meets in December and the abstracts were just released - hence the multiple press releases you will see in the news.
The drug was approved last week for the front line treatment of "typical patients" with CLL (they tended to be older and sicker than the FCR crowd). Our center has had the opportunity to study the drug extensively and in the surrounding news coverage, one of my patients was featured in local news. I think it is a nice story about a person taking the drug. I encourage you to watch it (note this was different study design than CLL11, there was no chlorambucil in this study).
The reason for the press release today is the big news that we had been expecting / waiting for to show that GA-101 (obinutuzumab, gazyva) looks like it did quite a bit better than rituximab. If you recall, at ASCO, they did a presentation where they compared chlorambucil (C) alone to C-Rituximab and a second comparison of C alone to C-Obinutuzumab. They did not release the comparison that everyone wanted to see which was the C-Rituximab versus C-Obinutuzumab. That is what is in the press release and will be presented in the plenary session at ASH in December.
The "progression free survival" is actually two separate criteria: 1) alive AND 2) no relapse of CLL. In the C-R arm the rate was 15 months and in the C-G arm it was 26 months - a full year better. The rest of the data will need to wait for the presentation - can't wait to see it.
Thanks for reading
Showing posts with label obinutuzumab. Show all posts
Showing posts with label obinutuzumab. Show all posts
Thursday, November 7, 2013
Friday, November 1, 2013
Gazyva (obinutuzumab) approved
It is really satisfying to work on a drug before it gets approved. I have had the opportunity to treat quite a few patients with both DLBCL and CLL with a drug that was approved earlier today called Gazyva (AKA: obinutuzumab or even GA-101). Some people just call it "G."
I was aware this day was coming for a little while as Genentech did a video series on several of my patients who had been treated with the drug so that they could use the video in news / media once the drug was approved.
Drug companies have to be EXTREMELY CAREFUL what they say publicly about their drug. Virtually every word they put out in advertisements gets carefully reviewed by the "commercial team" because if they make claims that are "off label" they can get into pretty deep trouble: see here.
I do not work for Genentech. I have not received any direct payment from them (they do provide research funding to my organization - US Oncology for studies we have performed). I have declined offers to be on a "speakers board" where I would receive compensation for speaking about their drug. In short, I am not bound by the same restrictions they are - so I thought I might share my thoughts.
I really think that this drug is a big deal in CLL - and they can't say it. In NHL the answer is still up in the air.
"Minimal residual disease" is a term we apply to a sensitive type of test (flow cytometry) where we can look for very small amounts of CLL in either the blood or the marrow. Patients can be categorized as MRD negative, MRD positive, or MRD intermediate. Not surprisingly, the less CLL you find, the longer the response lasts. I desperately need to do another post about MRD because I think it is how we are going to be comparing the efficacy of new drugs in the future.
If you look at data from the german CLL8 study in which FC was compared to FCR, the rate of achieving minimal residual disease negativity in the FCR arm was about 50%. If you look at the patients in the CLL11 study (that served as the basis for approval for this drug) the rate of MRD negativity in the GA101 / chlorambucil arm was about 30%. Since the MRD negativity to chlorambucil alone arm was a big fat zero, you can attribute most of the MRD activity to the GA-101.
What is remarkable to me is that you can get rates of MRD negativity of 30% with an antibody. I can tell you that ofatumumab, rituximab, and alemtuzumab can't touch that. Indeed, MRD negativity to the rituximab plus chlorambucil arm was only 8%. The FDA granted approval on the basis of the improvement of GA-101 plus chlorambucil over chlorambucil alone. There is no mention in the approval of the difference between the GA-101 plus chlorambucil versus the rituximab plus chlorambucil. Indeed, if you look at the graphs of how patients do, it is pretty apparent that GA-101 (obinutuzumab) is better than the rituximab arm - but since that is not what the data that supported approval, they cannot make that statement.
Rituximab is pretty much the only drug so far in CLL to improve overall survival. I am convinced that obinutuzumab is a much better drug in this disease. Median progression free survival for R-Chlorambucil was 15 months while it was 23 months for G-Chlorambucil. I have written a prior post about what makes GA-101 different. Until the FDA is able to review that arm of the study (which simply takes longer to evaluate because the data isn't yet "mature") - Genentech can't say that.
So how will the drug be used? Insurance will be the police making sure it is used according to the label. Every insurance company will have its own policies so some may allow off label use, some won't. The drug is approved in combination with chlorambucil for front line therapy of patients with CLL. Genentech is making much use of the word, "typical patients." That is because the average age of the patients in the study was 73 years old. Since that fits the exact age for average age for first therapy in CLL they like the word "typical." Others have used the term "elderly." I guess I sort of agree with their word. Keep in mind the average age in the FCR front line study was 62 years old. Those 11 years are enormously important.
Chlorambucil is hardly ever used in North America (although common in much of Europe and Australia). In the US, I am guessing that many patients will use the drug alone (without chlorambucil). Chlorambucil really has a reputation that is pretty unfair. It is a good drug, but there are many that are better. In the right patient though, chlorambucil can be really helpful. There have been studies that have combined GA-101 with bendamustine or even FC. That data has not really seen the light of day so I would be nervous to use it in combination with those drugs just yet.
The main downside to GA-101 is the infusion reactions. I have compared rituxan to rolling thunder and GA-101 to lightning. On the first dose of either drug it is common in CLL for a patient to have either shortness of breath, low blood pressure, hives, etc. With rituximab, it seems like those can come and go. Every time you turn up the rate of the infusion the symptoms can start again. You resolve the problem by slowing down, giving more tylenol, benadryl, steroids and starting again. It can feel like the rolling thunder that goes on for minutes in a good east coast storm. With gazyva the reactions happen very early in the infusion and feel a little more severe. Once they are done though it seems they really don't come back - more like lightning. With either drug it is considerably less frequent to experience these reactions on the second or subsequent dose. My fantastic infusion nurses seemed to figure out that if you stop the infusion at the first sign of trouble, the reactions were very manageable in the patients we treated.
What I found shocking working with the drug was that when the infusion reactions had settled down, if you rechecked the blood counts they had almost normalized - even just a few milligrams into therapy and after only thirty minutes. My research nurses and lab manager asked me several times, "what did you do to that patient?" It defied our experience to see blood counts change so quickly.
I am pleased to see this drug get approved. It was always a dark horse in the race. Everyone has been focused on ibrutinib and idelalisib but I had my bets placed on this drug crossing the finish line first. I think it is a significant new option for docs who treat the disease - but more importantly, combining it with other new drugs will give us the option to achieve very successful results without chemotherapy. Keep in mind that Genentech is co-developing ABT-199 (GDC-0199) with Abvie. That will be their obvious drug to combine it with. Now that obinutuzumab has been approved though, any company can begin to combine their drugs with it. Pharmacyclics, Gilead, and Jannsen would be smart to start combining their BCR signal inhibitors with obinutuzumab. I bet MRD rates will be VERY impressive with such combinations!
Thanks for reading.
I was aware this day was coming for a little while as Genentech did a video series on several of my patients who had been treated with the drug so that they could use the video in news / media once the drug was approved.
Drug companies have to be EXTREMELY CAREFUL what they say publicly about their drug. Virtually every word they put out in advertisements gets carefully reviewed by the "commercial team" because if they make claims that are "off label" they can get into pretty deep trouble: see here.
I do not work for Genentech. I have not received any direct payment from them (they do provide research funding to my organization - US Oncology for studies we have performed). I have declined offers to be on a "speakers board" where I would receive compensation for speaking about their drug. In short, I am not bound by the same restrictions they are - so I thought I might share my thoughts.
I really think that this drug is a big deal in CLL - and they can't say it. In NHL the answer is still up in the air.
"Minimal residual disease" is a term we apply to a sensitive type of test (flow cytometry) where we can look for very small amounts of CLL in either the blood or the marrow. Patients can be categorized as MRD negative, MRD positive, or MRD intermediate. Not surprisingly, the less CLL you find, the longer the response lasts. I desperately need to do another post about MRD because I think it is how we are going to be comparing the efficacy of new drugs in the future.
If you look at data from the german CLL8 study in which FC was compared to FCR, the rate of achieving minimal residual disease negativity in the FCR arm was about 50%. If you look at the patients in the CLL11 study (that served as the basis for approval for this drug) the rate of MRD negativity in the GA101 / chlorambucil arm was about 30%. Since the MRD negativity to chlorambucil alone arm was a big fat zero, you can attribute most of the MRD activity to the GA-101.
What is remarkable to me is that you can get rates of MRD negativity of 30% with an antibody. I can tell you that ofatumumab, rituximab, and alemtuzumab can't touch that. Indeed, MRD negativity to the rituximab plus chlorambucil arm was only 8%. The FDA granted approval on the basis of the improvement of GA-101 plus chlorambucil over chlorambucil alone. There is no mention in the approval of the difference between the GA-101 plus chlorambucil versus the rituximab plus chlorambucil. Indeed, if you look at the graphs of how patients do, it is pretty apparent that GA-101 (obinutuzumab) is better than the rituximab arm - but since that is not what the data that supported approval, they cannot make that statement.
Rituximab is pretty much the only drug so far in CLL to improve overall survival. I am convinced that obinutuzumab is a much better drug in this disease. Median progression free survival for R-Chlorambucil was 15 months while it was 23 months for G-Chlorambucil. I have written a prior post about what makes GA-101 different. Until the FDA is able to review that arm of the study (which simply takes longer to evaluate because the data isn't yet "mature") - Genentech can't say that.
So how will the drug be used? Insurance will be the police making sure it is used according to the label. Every insurance company will have its own policies so some may allow off label use, some won't. The drug is approved in combination with chlorambucil for front line therapy of patients with CLL. Genentech is making much use of the word, "typical patients." That is because the average age of the patients in the study was 73 years old. Since that fits the exact age for average age for first therapy in CLL they like the word "typical." Others have used the term "elderly." I guess I sort of agree with their word. Keep in mind the average age in the FCR front line study was 62 years old. Those 11 years are enormously important.
Chlorambucil is hardly ever used in North America (although common in much of Europe and Australia). In the US, I am guessing that many patients will use the drug alone (without chlorambucil). Chlorambucil really has a reputation that is pretty unfair. It is a good drug, but there are many that are better. In the right patient though, chlorambucil can be really helpful. There have been studies that have combined GA-101 with bendamustine or even FC. That data has not really seen the light of day so I would be nervous to use it in combination with those drugs just yet.
The main downside to GA-101 is the infusion reactions. I have compared rituxan to rolling thunder and GA-101 to lightning. On the first dose of either drug it is common in CLL for a patient to have either shortness of breath, low blood pressure, hives, etc. With rituximab, it seems like those can come and go. Every time you turn up the rate of the infusion the symptoms can start again. You resolve the problem by slowing down, giving more tylenol, benadryl, steroids and starting again. It can feel like the rolling thunder that goes on for minutes in a good east coast storm. With gazyva the reactions happen very early in the infusion and feel a little more severe. Once they are done though it seems they really don't come back - more like lightning. With either drug it is considerably less frequent to experience these reactions on the second or subsequent dose. My fantastic infusion nurses seemed to figure out that if you stop the infusion at the first sign of trouble, the reactions were very manageable in the patients we treated.
What I found shocking working with the drug was that when the infusion reactions had settled down, if you rechecked the blood counts they had almost normalized - even just a few milligrams into therapy and after only thirty minutes. My research nurses and lab manager asked me several times, "what did you do to that patient?" It defied our experience to see blood counts change so quickly.
I am pleased to see this drug get approved. It was always a dark horse in the race. Everyone has been focused on ibrutinib and idelalisib but I had my bets placed on this drug crossing the finish line first. I think it is a significant new option for docs who treat the disease - but more importantly, combining it with other new drugs will give us the option to achieve very successful results without chemotherapy. Keep in mind that Genentech is co-developing ABT-199 (GDC-0199) with Abvie. That will be their obvious drug to combine it with. Now that obinutuzumab has been approved though, any company can begin to combine their drugs with it. Pharmacyclics, Gilead, and Jannsen would be smart to start combining their BCR signal inhibitors with obinutuzumab. I bet MRD rates will be VERY impressive with such combinations!
Thanks for reading.
Wednesday, October 9, 2013
The race tightens
In case you missed it, Gilead put out a major press release today:
Gilead to Stop Phase 3 Study 116 of Idelalisib in Chronic Lymphocytic Leukemia Early Because of Positive Risk-Benefit
Idelalisib is a very promising experimental agent for both NHL and CLL. I've written about it quite a few times previously. In CLL there is overwhelming enthusiasm regarding the multitude of new drugs on the very near horizon.
Obinutuzumab is an exciting new antibody that has been granted "breakthrough status" with the FDA. Most readers will be familiar with Ibrutinib which carries the same FDA designation. Idelalisib is another important experimental new therapy but was not awarded the same breakthrough status and was therefore considered by some to be "third place" in the horse race of approval. This announcement will really give them a significant boost.
The FDA is charged with determining if a new therapy is both, "safe" and "effective." The absolute best way to do that is perform a randomized / blinded / controlled phase III study in which half of patients are given a "standard of care" and the other half are given the experimental treatment. If patients do better on the experimental treatment the drug can be approved.
It is fair to ask, "what is a standard of care?" Sometimes in CLL - particularly in elderly individuals it isn't exactly clear from any real source what is "standard." Is "standard" what is commonly done by doctors or is "standard" the most rigorously studied and published "treatment regimen." In CLL, single agent rituximab does not have the enthusiastic endorsement of many thought leaders, but if you look at what is done in practice it represents nearly 30% of the treatment offered to elderly individuals. Is single agent rituxan therefore a good control? That will be answered by the FDA.
Another way drugs may be approved is on the basis of an "accelerated approval" where a drug company identifies an "unmet medical need." This is a population of patients with a specific disease who have exhausted all of their therapies and lack any good remaining / approved options. If you can show that your new drug is active in this setting, the FDA can give you a "conditional approval." The "condition" is that your approval depends upon you then completing an appropriate randomized phase III study.
This route of approval can be perilous. A really promising breast cancer drug was rejected by the FDA while going down this road because it was felt that not every patient had truly exhausted every single approved drug. After the company then completed a randomized phase III study with the same drug, they got approval this year. Unfortunately nearly three years passed between these two events.
If anyone is following the story closely - here is where things stand:
Obinutuzumab conducted a randomized phase III trial in FRONTLINE ELDERLY patients with CLL. The antibody has some pretty significant advantages and the FDA has granted both "breakthrough status" and "priority review"
Ibrutinib submitted their application to the FDA on the basis of a non randomized study and the FDA has granted breakthrough status in the 17P deleted population. I am not participating in the subsequent randomized phase III studies with this molecule but there are quite a few of them and accrual has been brisk. Will it be approved in this smaller subgroup of patients or all patients with relapsed CLL? The FDA will soon tell.
Idelalisib had taken the single arm strategy in follicular lymphoma refractory to both rituximab and an alkalating agent chemotherapy. They had seemed a little behind in CLL but now this announcement gives them a lot of new momentum. They reported that a randomized phase III study in CLL had to be terminated early because the benefit of the experimental arm was so significant.
The study consisted of half patients getting single agent rituximab WITH a placebo while the other half got rituximab WITH idelalisib (CAL-101 or GS-1101). This strategy would only be appropriate for older individuals with medical reasons not to give chemotherapy.
It is always nice when a study stops early for positive results - but keep in mind that the DSMB (data safety monitoring board) is NOT the same group as the FDA. Now the study closes. It sounds like patients on the control arm will be allowed to receive idelalisib. This may minimize the magnitude of the benefit that would have occurred if the study were to continue. Other drugs have been stymied at the FDA under similar circumstances.
Can't wait to see how this all plays out.
Thanks for reading
Jeff
Gilead to Stop Phase 3 Study 116 of Idelalisib in Chronic Lymphocytic Leukemia Early Because of Positive Risk-Benefit
Idelalisib is a very promising experimental agent for both NHL and CLL. I've written about it quite a few times previously. In CLL there is overwhelming enthusiasm regarding the multitude of new drugs on the very near horizon.
Obinutuzumab is an exciting new antibody that has been granted "breakthrough status" with the FDA. Most readers will be familiar with Ibrutinib which carries the same FDA designation. Idelalisib is another important experimental new therapy but was not awarded the same breakthrough status and was therefore considered by some to be "third place" in the horse race of approval. This announcement will really give them a significant boost.
The FDA is charged with determining if a new therapy is both, "safe" and "effective." The absolute best way to do that is perform a randomized / blinded / controlled phase III study in which half of patients are given a "standard of care" and the other half are given the experimental treatment. If patients do better on the experimental treatment the drug can be approved.
It is fair to ask, "what is a standard of care?" Sometimes in CLL - particularly in elderly individuals it isn't exactly clear from any real source what is "standard." Is "standard" what is commonly done by doctors or is "standard" the most rigorously studied and published "treatment regimen." In CLL, single agent rituximab does not have the enthusiastic endorsement of many thought leaders, but if you look at what is done in practice it represents nearly 30% of the treatment offered to elderly individuals. Is single agent rituxan therefore a good control? That will be answered by the FDA.
Another way drugs may be approved is on the basis of an "accelerated approval" where a drug company identifies an "unmet medical need." This is a population of patients with a specific disease who have exhausted all of their therapies and lack any good remaining / approved options. If you can show that your new drug is active in this setting, the FDA can give you a "conditional approval." The "condition" is that your approval depends upon you then completing an appropriate randomized phase III study.
This route of approval can be perilous. A really promising breast cancer drug was rejected by the FDA while going down this road because it was felt that not every patient had truly exhausted every single approved drug. After the company then completed a randomized phase III study with the same drug, they got approval this year. Unfortunately nearly three years passed between these two events.
If anyone is following the story closely - here is where things stand:
Obinutuzumab conducted a randomized phase III trial in FRONTLINE ELDERLY patients with CLL. The antibody has some pretty significant advantages and the FDA has granted both "breakthrough status" and "priority review"
Ibrutinib submitted their application to the FDA on the basis of a non randomized study and the FDA has granted breakthrough status in the 17P deleted population. I am not participating in the subsequent randomized phase III studies with this molecule but there are quite a few of them and accrual has been brisk. Will it be approved in this smaller subgroup of patients or all patients with relapsed CLL? The FDA will soon tell.
Idelalisib had taken the single arm strategy in follicular lymphoma refractory to both rituximab and an alkalating agent chemotherapy. They had seemed a little behind in CLL but now this announcement gives them a lot of new momentum. They reported that a randomized phase III study in CLL had to be terminated early because the benefit of the experimental arm was so significant.
The study consisted of half patients getting single agent rituximab WITH a placebo while the other half got rituximab WITH idelalisib (CAL-101 or GS-1101). This strategy would only be appropriate for older individuals with medical reasons not to give chemotherapy.
It is always nice when a study stops early for positive results - but keep in mind that the DSMB (data safety monitoring board) is NOT the same group as the FDA. Now the study closes. It sounds like patients on the control arm will be allowed to receive idelalisib. This may minimize the magnitude of the benefit that would have occurred if the study were to continue. Other drugs have been stymied at the FDA under similar circumstances.
Can't wait to see how this all plays out.
Thanks for reading
Jeff
Wednesday, September 11, 2013
Video update from IWCLL
I had the chance to meet up with Andrew Schorr in Germany at the IWCLL meeting. We taped this interview to provide an overview of where the new CLL drugs may best fit into an individuals treatment plan. Hopefully it is a good summary for you and puts things into a more focused perspective.
Andrew does a great job collecting the voices of many experts and putting them into one place. If you haven't made a contribution to his efforts, you might want to think about doing so. We are lucky to have him out on the front lines.
I apologize for being a little long winded in response to his questions. So much exciting stuff to talk about, I had a hard time containing myself.
Andrew does a great job collecting the voices of many experts and putting them into one place. If you haven't made a contribution to his efforts, you might want to think about doing so. We are lucky to have him out on the front lines.
I apologize for being a little long winded in response to his questions. So much exciting stuff to talk about, I had a hard time containing myself.
Wednesday, July 10, 2013
ASCO update 2013
Andrew Schorr and Brian Koffman have done a fantastic job putting together videos to help educate CLL patients about the state of the art in CLL. I appreciate the opportunity to interview with them - they are a great team and a fantastic resource for CLL patients looking for good information about what is out there.
In this interview we talked about a number of new investigational medications that many CLL patients have heard of including ibrutinib, idelalisib, obinituzumab, and ABT-199. Hopefully this gives some new insight into the importance of research participation.
In this interview we talked about a number of new investigational medications that many CLL patients have heard of including ibrutinib, idelalisib, obinituzumab, and ABT-199. Hopefully this gives some new insight into the importance of research participation.
Saturday, May 18, 2013
GA-101 aka. obinutuzumab in CLL
I love it when a drug comes out of nowhere to suddenly become the hottest thing around... The latest recipient of that distinction is obinutuzumab.
The annual mega-conference ASCO (american society of clinical oncology) starts up in the last few days of this month. There are a few big papers for CLL/NHL patients. I hope to capture the highlights over the next few weeks as I put out updates.
One thing to be VERY careful about is the misuse of the term, "significant." There is a huge difference between something that is "statistically significant" (ie. a comparison in which the results are unlikely to have occurred by chance) and "clinically significant" (ie. this makes a genuine difference for patients with the disease). Read my prior post about how things get mischaracterized as "significant."
So what are the big updates this year?
Ibrutinib is in a data lull between the mature reports of the early studies and the ongoing registration studies that have not yet reported. There is a fantastic piece about ibrutinib resistance that I put up a few days ago. Idelalisib is still reporting out the mature results of early studies. Phase III trials are ongoing. I've been after them to get their phase I studies published but they have been quite slow getting those out the door.
GA-101 (also named obinutuzumab) has a very important presentation. Rituxan comes off patent pretty soon - hopefully that would lower drug costs (although in this case - maybe not so much). While the regulators and industry are all tied up in knots over how to make a generic antibody - Roche has set out to make a better version of the drug - see my post on building a better CD20 antibody.
Our first peak into the "efficacy" of GA-101 came last year at ASH where it was compared straight up head to head with rituxan in relapsed indolent non-hodgkin's lymphoma. Patients got a dose of either drug once per week then once every two months for two years.
There was a suggestion that patients in the GA-101 arm had a higher response rate compared to rituxan. Unfortunately when you figured out how long the responses lasted it was pretty equal for both groups. It was interesting to watch the response. I think the sponsors were excited to see the increased response rate but a lot of investigators sort of yawned.... yup, just another CD20 antibody - not much to see here.
That is why this ASCO presentation of GA-101 in patients with CLL is so exciting - there is something really different here!
GA-101 was studied in the German CLL 11 study. This was a three arm study in which chlorambucil was compared to chlorambucil in combination with either rituximab or GA-101. The study included elderly (average age 73) individuals with decreased kidney function (necessary for fludarabine elimination from the body), or a bunch of other medical problems as defined by the Cumulative Illness Rating Scale (CIRS).
Addition of either rituxan or GA-101 thumped chlorambucil doubling the overall response rate from 30 to 60-70%. Complete response rate with chlorambucil came in with a whopping 0%, adding rituxan took it to 8%, and GA-101 got it to 22%. While the increased response rate was encouraging you could say that was the same in the other study listed above that wasn't quite as exciting.
The key to this being something really new was that the progression free survival went from 10 months with chlorambucil to 15 months with rituxan and 23 months with GA-101. To me that indicates that GA-101 is really doing something new / better than the stalwart rituximab. Infusion reactions were a bit more significant with GA-101.
For a variety of statistical considerations they did not directly compare the rituxan group to the GA-101 but looking at the raw numbers things look good for GA-101. In fact Genentech looks pretty happy with the data and sounds like the drug has been labeled "breakthrough drug" with the FDA indicating a fast track for approval in near future!
GA-101 has been circling around under the radar for a little while. While the stories of patients on the new B Cell receptor inhibitors have been very exciting, I don't think there was quite the buzz out there for this drug. I love it when we get a nice surprise!
The annual mega-conference ASCO (american society of clinical oncology) starts up in the last few days of this month. There are a few big papers for CLL/NHL patients. I hope to capture the highlights over the next few weeks as I put out updates.
One thing to be VERY careful about is the misuse of the term, "significant." There is a huge difference between something that is "statistically significant" (ie. a comparison in which the results are unlikely to have occurred by chance) and "clinically significant" (ie. this makes a genuine difference for patients with the disease). Read my prior post about how things get mischaracterized as "significant."
So what are the big updates this year?
Ibrutinib is in a data lull between the mature reports of the early studies and the ongoing registration studies that have not yet reported. There is a fantastic piece about ibrutinib resistance that I put up a few days ago. Idelalisib is still reporting out the mature results of early studies. Phase III trials are ongoing. I've been after them to get their phase I studies published but they have been quite slow getting those out the door.
GA-101 (also named obinutuzumab) has a very important presentation. Rituxan comes off patent pretty soon - hopefully that would lower drug costs (although in this case - maybe not so much). While the regulators and industry are all tied up in knots over how to make a generic antibody - Roche has set out to make a better version of the drug - see my post on building a better CD20 antibody.
Our first peak into the "efficacy" of GA-101 came last year at ASH where it was compared straight up head to head with rituxan in relapsed indolent non-hodgkin's lymphoma. Patients got a dose of either drug once per week then once every two months for two years.
There was a suggestion that patients in the GA-101 arm had a higher response rate compared to rituxan. Unfortunately when you figured out how long the responses lasted it was pretty equal for both groups. It was interesting to watch the response. I think the sponsors were excited to see the increased response rate but a lot of investigators sort of yawned.... yup, just another CD20 antibody - not much to see here.
That is why this ASCO presentation of GA-101 in patients with CLL is so exciting - there is something really different here!
GA-101 was studied in the German CLL 11 study. This was a three arm study in which chlorambucil was compared to chlorambucil in combination with either rituximab or GA-101. The study included elderly (average age 73) individuals with decreased kidney function (necessary for fludarabine elimination from the body), or a bunch of other medical problems as defined by the Cumulative Illness Rating Scale (CIRS).
Addition of either rituxan or GA-101 thumped chlorambucil doubling the overall response rate from 30 to 60-70%. Complete response rate with chlorambucil came in with a whopping 0%, adding rituxan took it to 8%, and GA-101 got it to 22%. While the increased response rate was encouraging you could say that was the same in the other study listed above that wasn't quite as exciting.
The key to this being something really new was that the progression free survival went from 10 months with chlorambucil to 15 months with rituxan and 23 months with GA-101. To me that indicates that GA-101 is really doing something new / better than the stalwart rituximab. Infusion reactions were a bit more significant with GA-101.
For a variety of statistical considerations they did not directly compare the rituxan group to the GA-101 but looking at the raw numbers things look good for GA-101. In fact Genentech looks pretty happy with the data and sounds like the drug has been labeled "breakthrough drug" with the FDA indicating a fast track for approval in near future!
GA-101 has been circling around under the radar for a little while. While the stories of patients on the new B Cell receptor inhibitors have been very exciting, I don't think there was quite the buzz out there for this drug. I love it when we get a nice surprise!
Saturday, August 18, 2012
Building a better CD20 antibody?
Rituxan was an unbelievable breakthrough drug in the treatment of all sorts of B cell lymphoid cancers (CLL / NHL) as well as a lot of autoimmune conditions to boot. At the time it was put into the patients, the idea of using therapeutic antibodies to treat cancer had not really been done. Skeptics abounded. As soon as it was tried, it was immediately obvious that there had been a breakthrough. One theme I continually revist is that the immune system can be a very powerful cancer fighter when properly directed. Rituxan was one of the first ways to focus this aspect of the immune system to fight off lymphoma.
You make antibodies to fight off the flu, e. coli, etc. Instead of the naturally occuring variety of antibodies, rituxan is a synthesized antibody designed to fight off B-Cells (ie. the cells that give rise to lymphoma and CLL). Rituxan binds onto the outside of the cancer cell (on a marker known as CD20) and has about 4-5 ways to kill the cell.
15 years later, hundreds of thousands of patients have been treated. As a single agent nearly 70% of patients with untreated follicular lymphoma will respond and in many cases the responses can be very durable. In most situations where giving chemotherapy for CLL/NHL is good, giving it together with rituxan is better. Not bad for a drug that has few of the side effects of traditional chemotherapy!
Not long after Rituxan demonstrated its value, lots of science went toward understanding why rituxan does or doesn't work. With the accumulated knowledge, different companies have sought to make a better version of the drug.
Ofatumumab was the next CD20 antibody to be approved. The main improvements in ofatumumab was more sturdy binding to CD20, binding at a different location on CD20, and a better job "fixing complement." Complement is a set of "executioner proteins" that get recruited from the circulation when there is enough antibody bound to the outside of a cell. "Fixing complement" just means it does a better job attracting those proteins to bind to the outside of the cell and punch holes through the membrane.
GA-101 is an ant-CD20 antibody currently in clinical trials in both CLL/NHL. GA-101 (aka obinutuzumab) does several things new. It binds to CD20 in a different orientation. Imagine an antibody like the letter "Y" The top of the "Y" is the little "grabber" part that identifies its target while the bottom part of the "Y" sticks out and alerts the immune system. GA-101 binds more vertically which sticks the action end out there better for the rest of the immune system to see. Rituxan binds more flat to the cell and the action end sort of gets burried on the surface of the cell. GA-101 also has a more flexible "hinge region" (where the "Y" splits) which is supposed to help bring together the different proteins better. GA-101 also "engineers out" the complement activity and instead "engineers in" better ADCC. ADCC (antibody dependent cellular cytotoxicity) is the term that describes when a "killer cell" attackes a target cell because it is coated with antibody. Finally there is a somewhat poorly characterized process by which antibodies can cause direct cell killing. This is supposedly enhanced by antibodies known as "Type 2" antibodies (not really worth explaining this one, except that Rituxan / Ofatumumab are Type 1)
So far, there are not a lot of studies that clinically compare the different anti CD20 antibodies head to head. Ofatumumab initially tried to get an FDA approval in follicular lymphoma patients considered refractory to Rituximab. Results didn't really impress all that much. Based upon FDA approval strategies, it also tried to gain approval in CLL patients were refractory to fludarabine AND campath (or bulky fludarabine refractory where campath doesn't work well). This worked better and led to the approval of ofatumumab in CLL. The drug has not yet gained a high utilization in CLL.
GA-101 is owned by Genentech and with Rituxan likely to go off patent in the future, they are working hard to make GA-101 the standard-bearer. At ASH 2011 there were a lot of clinical papers with GA-101 but the most notable was a head to head comparison of GA-101 to Rituxan in patients with relapsed follicular lymphoma. GA-101 had twice the response rate though the duration of response was not a lot different. Hard to say if that is a glass half full or half empty - trying to extrapolate to different NHL / CLL situations it may depend on the context. Increasing a response rate in DLBCL might be very important whereas PFS prolongation may be more important in follicular lymphoma. Furthermore, we should probably consider that the activity of one antibody may be better in CLL while a different set of characteristics may make a different antibody better in follicular lymphoma.
Perhaps the cleanest way to figure if a drug is active is in the previously untreated patients. Ofatumumab was studied in this setting and reported at ASH. GA-101 has been evaluated in front line CLL and I found this news story anecdote to be pretty exciting though you must be very careful with anecdotes and no formal reports are available. Rituximab was evaluated in relapsed patients way back in the early 2000s with pretty modest single agent activity, though improved with higher dosing of the drug or greater frequency (another way of increasing the dose).
You can bet you will hear a lot about "better versions of rituxan." Look for head to head comparisons or results that are substantially different from prior series. Rituxan was definitely a pioneer, but I fully expect we will be able to build a better treatment. Here is a review published in ASH that goes over a lot of the information above and describes some of the other strategies to improve upon rituxan.
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